Northwestern  University 

EVANSTON,  Iw,. 


Arsenated  Benzophenone 
and  its  Derivatives 


A  DISSERTATION 


SUBMITTED  TO  THE  FACULTY  OF  THE  GRADUATE  SCHOOL 

IN  CANDIDACY  FOR  THE  DEGREE  OF 

DOCTOR  OF  PHILOSOPHY 


DEPARTMENT  OF  CHEMISTRY 


By  HAROLD  C.  CHEETHAM 


E ASTON,  PA.: 
PRESS  OF  THE  ESCHENBACH  PRINTING  CO. 

1922 


Northwestern   University 

EVANSTON,  ILL. 


Arsenated  Benzophenone 
and  its  Derivatives 


A  DISSERTATION 


SUBMITTED  TO  THE  FACULTY  OF  THE  GRADUATE  SCHOOL 

IN  CANDIDACY  FOR  THE  DEGREE  OF 

DOCTOR  OF  PHILOSOPHY 


DEPARTMENT  OF  CHEMISTRY 


By  HAROLD  C.  CHEETHAM 


EASTON,  PA.: 
PRESS  OF  THE  ESCHENBACH  PRINTING  CO. 

1922 


ARSENATED    BENZOPHENONE    AND    ITS    DERIVATIVES.1 

Introduction. 

Arsenic  in  an  aromatic  nucleus  does  not  interfere  with  many  typical 
organic  reactions.  The  Friedel  and  Crafts  reaction,  however,  has  found 
but  limited2  application  in  organic  arsenical  chemistry.  With  a  view  to 
determining  whether  ar-senated  benzoyl  chloride  would  enter  into  the 
Friedel  and  Crafts  reaction,  thus  yielding  a  new  type  of  arsenic  compound 
of  possible  therapeutic  value,3  the  work  described  in  this  paper  was  under- 
taken. 

1  This  work  was  done  under  a  grant  from  the  Interdepartmental  Hygiene  Board, 
Washington,  D.  C.,  Dr.  T.  A.  Storey,  Sec'y. 

2  Lewis,  Lowry  and  Bergeim,  /.  Am.  Chem.  Soc.,  43,  892  (1921). 

8  Therapeutic  tests  upon  new  compounds  developed  under  this  grant  are  being 
conducted  by  Dr.  A.  S.  Loevenhart,  Department  of  Pharmacology,  University  of 
Wisconsin. 


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It  has  been  found  that  dichloro-^-arsinobenzoyl  chloride  condenses 
quite  readily  with  aromatic  hydrocarbons  and  phenyl  ethers  in  the  presence 
of  anhydrous  aluminum  chloride  using  carbon  disulfide  as  a  solvent.  When 
benzene  was  coupled  with  the  arsenated  acid  chloride,  some  benzophenone 
itself  was  found  among  the  products  of  the  reaction,  and  identified  by 
conversion  into  its  oxime,  melting  at  140°.  The  formation  of  benzo- 
phenone establishes  the  course  of  the  main  reaction  as  follows. 

0  =  CC1  (A1CU)    O  =  C 

A 

+     C,H,  —  >•  +     HC1. 

AsCl.  AsCl, 

When  the  reaction  is  too  vigorous,  de-arsenation  of  the  compound  results. 


+  HC1  —  -*>  +     AsCb. 

AsCl2 

The  amount  of  benzophenone  never  exceeded  10%,  usually  running 
0.5-1%,  while  the  yield  of  arsenated  benzophenone  was  50-60%.  That 
the  arsenated  product  is  a  ketone  is  shown  by  the  fact  that  it  reacts  with 
hydroxylamine  to  form  an  oxime  of  the  formula  C6H5C=  (NOH)C6H4- 
AsO3H2.  Furthermore,  de-arsenation  of  the  pure  product  by  long  refluxing 
with  cone,  hydrochloric  acid  yields  benzophenone. 

Experimental. 

Preparation  of  Benzarsonic  Acid.  —  Since  a  considerable  quantity  of  benzarsonic 
acid  (^-carboxy-phenylarsonic  acid)  was  required  for  this  work,  a  comparative  study 
was  made  of  the  available  methods  of  preparation.  Of  the  three  processes  described 
in  the  literature,  the  first  involves  the  oxidation  of  p-tolylarsonic  acid  by  means  of 
alkaline  potassium  permanganate.4  The  yield  is  about  60%  of  the  calculated  amount, 
but  the  process  is  slow  and  tedious.  A  second  method  uses  dil.  nitric  acids  in  sealed 
tubes  in  the  oxidation  of  ^-tolylarsonic  acid.  The  yield  is  practically  quantitative, 
but  working  in  sealed  tubes  at  150°  limits  the  amount  of  material,  and  the  high  pressure 
developed  breaks  a  large  percentage  of  the  tubes.  In  the  third  process,  arsanilic  acid 
is  diazotized,6  the  cyanogen  group  introduced  through  the  Sandmeyer  reaction,  and 
hydrolyzed  to  benzarsonic  acid.  The  yield  is  uncertain  and  the  method  expensive. 

A  more  economical  and  time-saving  method  was  developed  as  follows.  £-Nitro- 
benzoic  acid  is  reduced  to  p-aminobenzoic  acid,  which  is  converted  to  the  corresponding 
arsonic  acid  by  Bart's  reaction.1 

Reduction  of  £-Nitrobenzoic  Acid.  —  The  method  of  Jacobs  and  Heidelberger8  was 

4  La  Coste,  Ann.,  208,  1  (1881). 

5  Michaelts,  ibid..  320,  303  (1902);  Ber..  48,  870  (1915). 

6  Bertheim,  Ber.,  41,  1857  (IPOS). 

7  Bart,  Ger.  pat.  250,264  and  254.345. 

8  Jacobs  and  Heidelberger  /.  Am.  Chem.  Soc.,  3Q,  1437  (1917). 


applied  with  excellent  results  in  this  reduction.  Twenty-five  g.  of  £-nitro-benzoic  acid 
(technical)  is  dissolved  in  a  small  amount  of  warm  dil.  ammonium  hydroxide  and  poured 
with  stirring  into  a  boiling  solution  of  300  g.  of  commercial  ferrous  sulfate  crystals  in 
400  cc.  of  water.  About  100  cc.  of  cone,  ammonium  hydroxide  is  cautiously  added, 
and  the  boiling  continued  for  5  minutes.  The  product  is  filtered  hot  after  the  addition 
of  50  cc.  of  ammonium  hydroxide.  On  acidifying  the  filtrate  with  acetic  acid,  p-ammo- 
benzoic  acid  crystallizes  in  long,  light  yellow 'needles ;  m.  p.,  186°;  yield,  85-90%. 

Conversion  of  p-Aminobenzoic  Acid  to  Benzarsonic  Acid. — The  method  of  Bart 
is  applied  as  follows.  Fifty  g.  of  ^-aminobenzoic  acid  is  dissolved  in  750  cc.  of  water 
with  75  cc.  of  cone,  hydrochloric  acid  and  diazotized  in  the  usual  manner,  using  26  g. 
of  sodium  nitrite.  The  arsenite  solution  is  prepared  by  dissolving  46  g.  of  arsenic 
trioxide  in  400  cc.  of  water  with  54  g.  of  sodium  hydroxide.  Twenty  cc.  of  6  N  copper 
sulfate  solution  is  now  added.  The  diazo  solution  is  slowly  poured  into  the  arsenite- 
solution  with  vigorous  stirring,  the  temperature  being  held  at  20°.  The  alkaline  solution 
is  then  warmed  on  the  water-bath  to  60°  until  the  evolution  of  nitrogen  ceases,  when 
it  is  acidified  with  hydrochloric  acid.  A  water-insoluble  flocculent  precipitate  is  filtered 
and  discarded.  The  filtrate  on  concentrating  to  500  cc.,  cooling,  and  scratching, 
deposits  colorless  crystals  of  benzarsonic  acid.  The  yield  is  50-60%. 

Preparation  of  Dichloro-/>-arsinobenzoyl  Chloride,9  Cl-2AsC6H4COCl. — Twenty  cc. 
of  phosphorus  trichloride  in  20  cc.  of  chloroform  is  slowly  added  to  25  g.  of  benzarsonic 
acid  suspended  in  100  cc.  of  cold  chloroform.  After  warming  to  complete  the  reaction, 
20  g.  of  phosphorus  pentachloride  is  added  at  once.  When  this  second  reaction  has 
been  completed  by  heating  the  solution  on  a  water-bath  for  10  to  15  minutes,  the  mixture 
is  fractionated  in  vacua.  Dichloro-£-arsino-benzoyl  chloride  passes  over  at  190-195° 
under  20-25  mm.  pressure.  The  yield  is  75-80%.  In  later  runs  with  larger  amounts 
the  fractionation  was  omitted,  the  material  being  used  directly  for  the  condensation 
with  aluminum  chloride. 

Preparation  of  Benzophenone-/>-arsenious  Oxide,  C6H5COC6H4As  =  O. — Twenty  g. 
of  the  above  acid  chloride,  dissolved  in  100  cc.  of  dry  carbon  disulfide,  is  added  to  25  cc. 
of  dry  benzene.  Twenty-five  g.  of  anhydrous  aluminum  chloride  is  then  added  in 
5g.  portions  to  reduce  the  intensity  of  the  reaction.  After  warming  at  50°  on  the  water- 
bath  for  2  hours  under  a  reflux  condenser,  the  reaction  mixture  is  poured  while  warm  on 
300  g.  of  cracked  ice.  Ten  cc.  of  cone,  hydrochloric  acid  is  added,  and  the  carbon 
disulfide  and  excess  benzene  removed  by  steam  distillation.  The  reaction  flask  now 
contains  a  clear  aqueous  solution  and  a  gummy  substance  which  adheres  to  the  walls 
of  the  flask.  The  aqueous  solution,  which  contains  the  hydrated  aluminum  chloride 
and  some  £-carboxy-phenylarsenious  acid  is  decanted  and  discarded.  Four  hundred 
cc.  of  dil.  sodium  carbonate  solution  and  50  cc.  of  6  N  sodium  hydroxide  solution  are 
added  to  the  flask  and  warmed  to  decompose  the  gummy  mass  which  gradually  goes  into 
solution.  After  filtering  and  cooling,  benzophenone-^-arsenious  oxide  is  precipitated 
in  an  amorphous  condition  by  dil.  hydrochloric  acid.  The  yield  is  60%.  It  is  slightly 
soluble  in  boiling  water,  absolute  alcohol,  benzene,  and  ether,  and  easily  soluble  in  warm 
alkalies. 

Analyses.  Subs.,  0.2442,  0.1643:  34.5  cc.,  23.3  cc.  of  0.0521  N  iodine  solution. 
Calc.  for  Ci3H902As:  As,  27.57.  Found:  27.59,27.69. 

Benzophenone-£-arsenious  Acid,  CeHf.COCeHUAstOH^. — The  above  oxide,  after 
boiling  for  several  hours  with  a  large  amount  of  water,  yields  a  small  quantity  of  fine 
crystals  insoluble  in  ether  or  benzene,  easily  soluble  in  cold  alkalies,  and  somewhat 
soluble  in  absolute  alcohol.  It  is  apparently  the  hydrated  oxide. 

9  Poulenc,  French  pat.  441,215, 


Analyses.  Subs.,  0.2681:  46.95  cc.  of  0.0389  N  iodine  solution.  Calc.  for 
Ci3HiiO3As:  As,  25.86.  Found:  25.57. 

Benzophenone-£-arsonic  Acid,  Cel^COCeEUAsOsHj. — The  oxide  is  dissolved  in 
warm  dil.  sodium  hydroxide  and  a  slight  excess  of  the  calculated  amount  of  3%  hydrogen 
peroxide  solution  added.  After  warming  for  5  minutes,  the  solution  is  acidified  with 
hydrochloric  acid,  which  precipitates  at  once  the  arsonic  acid.  From  large  volumes  of 
boiling  water,  recrystallization  yields  lustrous  clusters  of  elongated  plates.  The  yield 
is  quantitative.  The  crystals  soften  at  195°  but  do  not  melt  below  260°  The  substance 
is  insoluble  in  cold  water,  benzene,  and  ether,  and  soluble  in  alkalies,  ethyl  alcohol, 
and  warm  glacial  acetic  acid. 

Analyses.  Subs.,  0.2214,  0.1579:  27.8  cc.,  19.7  cc.  of  0.0521  N  iodine  solution. 
Calc.  for  Ci3HnO4As:  As,  24.51.  Found:  24.52,  24.35. 

Oxime  of  Benzophenone-£-arsonic  Acid,  C6HsC=(NOH)C6H4AsO3H2.— Ten  g.  of 
benzophenone-/>-arsonic  acid  is  heated  in  a  slightly  alkaline  alcoholic  solution  with  5  g. 
of  hydroxylamine  sulfate  on  the  water-bath  for  2  hours.  After  cooling  and  acidifying 
with  dil.  sulfuric  acid,  the  product  is  recrystallized  from  hot  water,  yielding  fine  colorless 
needles  which  do  not  melt  below  260°.  The  yield  is  80%. 

Analyses.  Subs.,  0.4611:  12.8  cc.  of  0.108  N  sodium  hydroxide  (Kjeldahl). 
Calc.  for  CuHizO^As:  N,  4.36.  Found:  4.20. 

Subs.,  0.1390:  17.15  cc.  of  0.0497  N  iodine  solution.  Calc.  for  Ci3Hi2O4NAs: 
As,  23.36.  Found:  23.01. 

Mononitro-benzophenone-^-arsonic  Acid,  (NOi)  C^COC^HiAsOaHj. — Thirty-five 
g.  of  fuming  nitric  acid  (sp.  gr.  1.5)  is  added  to  4  g.  of  benzophenone-/>-arsonic  acid  and 
the  solution  heated  on  the  water-bath  for  one  hour.  After  dilution  with  50  cc.  of  water, 
the  mixture  is  slowly  evaporated  to  a  thick  syrup  to  expel  the  nitrous  fumes.  After 
two  recrystallizations  from  hot  water,  2  g.  of  fine,  light  yellow  needles  were  obtained. 

Analyses.  Subs.,  0.5385:  12.95  cc.  of  0.108  N  sodium  hydroxide  (Kjeldahl). 
Calc.  for  Ci3H10O6NAs:  N,  3.98.  Found:  3  65. 

Subs.,  0.3719:  40.45  cc.  of  0.0521  N  iodine  solution.  Calc.  for  Ci3Hi0O6NAs, 
As,  21.36.  Found:  21.24. 

4-Methyl-benzophenone-4'-arsenious  Oxide,  CHsC^COCel^AsO. — This  com- 
pound is  made  by  substituting  toluene  for  benzene  in  the  procedure  described  above  for 
benzophenone-£-arsenious  oxide.  The  yield  is  about  50%.  Due  to  its  amorphous 
character,  the  product  is  difficult  to  purify,  and  arsenic  analyses  give  results  0.5-0.7% 
low.  Its  hydrate  is  made  by  prolonged  boiling  with  a  large  volume  of  water,  giving  a 
small  quantity  of  fine,  needle-like  crystals,  soluble  in  alkalies,  insoluble  in  ether,  or 
benzene,  and  somewhat  soluble  in  ethyl  alcohol. 

Analyses.  Subs.,  0.2658,  0.1904:  22.5  cc.,  16.05  cc.  of  0.0772  N  iodine  solution. 
Calc.  for  Ci4Hi3O3As:  As,  24.67.  Found:  24.50,24.40. 

4-Methyl-benzophenone-4'-arsonic  Acid,  CHgCaH^.OQjH^sOsK^.— Oxidation  of 
the  above  oxide  in  warm  alkaline  solution  by  means  of  3%  hydrogen  peroxide  gives  a 
good  yield  of  the  corresponding  arsonic  acid,  which  crystallizes  from  hot  water  in 
transparent  plates,  easily  soluble  in  alkalies,  somewhat  soluble  in  ethyl  alcohol,  insoluble 
in  ether,  benzene,  etc.  The  crystals  did  not  melt  below  260°. 

Analysis.  Subs.,  0.1330:  15.9  cc.  of  0.0521  N  iodine  solution.  Calc.  for  Ci4Hi3O4- 
As:  As,  23.43.  Found:  23.34. 

The  condensation  of  dichloro-p-arsinobenzoyl  chloride  with  the  phenyl  ethers 
proceeds  very  smoothly,  giving  60-75%  yields.  In  each  case  the  substituted  arsenious 
oxides  were  found  to  be  amorphous  and  difficult  to  purify,  and  they  yielded  no 


crystalline  hydrates.  They  were  therefore  oxidized  to  the  corresponding  arsonic  acids, 
which  are  well  crystallized  and  easily  purified. 

4-Methoxy-benzophenone-4  '-arsonic  Acid,  CHsOCe^COCeH^AsOal^.—  Starting 
with  anisole  in  place  of  benzene  in  the  original  condensation  and  oxidizing  the  inter- 
mediate arsine  oxide  without  attempting  to  isolate  it,  the  corresponding  arsonic  acid  is 
obtained  in  60-70%  yield  after  recrystallization  from  large  volumes  of  boiling  water. 

Analysis.  Subs.,  0.3319:  37.4  cc.  of  0.0521  N  iodine  solution.  Calc.  for  CuHi3O5- 
As:  As,  22.32.  Found:  22.01. 

4-Ethoxy-benzophenone-4  '-arsonic  Acid,  CjH6OC6H4COC6H,AsO3Ha.  —  Following 
the  same  procedure,  phenetole  gives  a  55%  yield  of  the  ethoxy-derivative.  As  the  mole- 
cular weight  increases,  the  solubility  of  these  arsonic  acids  in  water  decreases,  so  that  it 
becomes  difficult  to  use  water  as  a  solvent  for  recrystallization.  Glacial  acetic  acid  or 
95%  ethyl  alcohol  is  found  satisfactory. 

Analysis.  Subs.,  0.2193:  24.95  cc.  of  0.0497  N  iodine  solution.  Calc.  for 
Ci5H15O6As:  As,  21.42.  Found:  21.21. 

4-Phenoxy-benzophenone-4  '-arsonic  Acid,   CeHsOCeHiCOCel^AsOsI^.  —  This  ar- 


water, even  at  100°.  It  is  easily  crystallized  from  hot  glacial  acetic  acid  or  95%  alcohol. 
giving  colorless  platelets,  which  do  not  melt  below  260°. 

Analyses.  Subs.,  0.1745:  16.7  cc.  of  0.0521  N  iodine  solution.  Calc.  for  Ci9Hi5- 
OsAs:  As,  18.84.  Found:  18.69. 

Similar  compounds  have  been  made  from  the  ortho  and  meta  homologs  of  dichloro- 
p-arsinobenzoyl  chloride,  and  will  be  reported  later. 

Summary. 

1.  It   has   been   found   possible   to   condense   dichloro-p-arsinobenzoyl 
chloride  with  benzene,  toluene,  anisole,  phenetole,  and  diphenyl  ether 
in  the  presence  of  aluminum  trichloride  with  carbon  disulfide  as  a  solvent. 

2.  Properties  and  directions  for  preparing  the  following  compounds 
are   given:     benzophenone-/?-arsenious   oxide,    benzophenone-^-arsenious 
acid,  benzophenone-£-arsonic  acid  and  its  oxime  and  mononitro  derivative, 
4-methyl-benzophenone-4  '-arsenic    acid,   4-methoxy-benzophenone-4  '-ar- 
sonic  acid,   4-ethoxy-benzophenone-4  '-arsonic   acid,   and  4-phenoxy-ben- 
zophenone-4  '-arsonic  acid. 

3.  An  improved  method  for  the  preparation  of  benzarsonic  acid  'has 
been  developed. 


The  author  wishes  to  thank  Dr.  W.  Lee  Lewis  for  his  kindly  guidance 
and  to  express  his  appreciation  of  him,  both  as  a  friend  and  a  teacher. 


:..: ; 


\ 


Photomount 
Pamphlet 

Binder 
Gaylord  Bros. 

Makers 
Stockton,  Calif. 

PAT.  JAN.  21.  1908 


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